DNA nanomachines reveal an adaptive energy mode in confinement-induced amoeboid migration powered by polarized mitochondrial distribution
Yixin Liu, Yixin Liu, Yajun Wang, Yang Du, Wei Liu, Xuedong Huang, Zihui Fan, Jiayin Lu, Runqiu Yi, Xiaowei Xiang, Xinwei Xia, Hongzhou Gu, Yan‐Jun Liu, Yan‐Jun Liu, Baohong Liu
Abstract
Energy metabolism is highly interdependent with adaptive cell migration in vivo. Mechanical confinement is a critical physical cue that induces switchable migration modes of the mesenchymal-to-amoeboid transition (MAT). However, the energy states in distinct migration modes, especially amoeboid-like stable bleb (A2) movement, remain unclear. In this report, we developed multivalent DNA framework-based nanomachines to explore strategical mitochondrial trafficking and differential ATP levels during cell migration in mechanically heterogeneous microenvironments. Through single-particle tracking and metabolomic analysis, we revealed that fast A2-moving cells driven by biomimetic confinement recruited back-end positioning of mitochondria for powering highly polarized cytoskeletal networks, preferentially adopting an energy-saving mode compared with a mesenchymal mode of cell migration. We present a versatile DNA nanotool for cellular energy exploration and highlight that adaptive energy strategies coordinately support switchable migration modes for facilitating efficient metastatic escape, offering a unique perspective for therapeutic interventions in cancer metastasis.